Delivery system

ABSTRACT

The present invention relates to a new delivery system for nutritional ingredients (nutraceuticals). These nutritional ingredients are useful for gut and metabolic health in monogastric animals, especially in humans.

This application is the U.S. national phase of International Application No. PCT/EP2018/079662 filed 30 Oct. 2018, which designated the U.S. and claims priority to EP Patent Application No. 17199806.5 filed 3 Nov. 2017, the entire contents of each of which are hereby incorporated by reference.

The present invention relates to a new delivery system of water-soluble vitamins (i.e. B vitamins (especially B2)) for the large intestine. These nutritional ingredients are useful for gut and metabolic health in monogastric animals (such as swine and poultry as well as fish), especially in humans.

During the last few year, an increase in consumer interest in products that promote gut health could be observed. Many new products came on the market and where accepted widely by the consumers.

There has also been increased investigation into the potential effects of gut microbiota on metabolism and immunity, as well as obesity, inflammation, cardiovascular disease and diabetes.

It is known, that Riboflavin (vitamin B2), when delivered to the large intestine, has a beneficial effect on growth of Faecalibacterium prausnitzii, which is a marker species for a healthy gut. EP2914135 describes use of riboflavin for the selective stimulation of F. prausnitzii. However, very high dosages of riboflavin are required, because the main part is already destroyed or absorbed before reaching the large intestine.

Release in the small or large intestine is usually achieved with controlled release capsules or tablets. The active substances are incorporated in a capsule or tablet that is coated with one or more coatings that lead to controlled release. However, tablets and capsules as delivery system have several drawbacks. The amount of active that can be incorporated in a single tablet or capsule limited by the available volume. Especially very young and elderly patients have difficulties with swallowing tablets or capsules. Residence time of capsules and tablets in the stomach is very variable and release is very punctual, which may lead to very high local concentrations of the active, which may cause detrimental effects.

Multiparticulate forms like powders, granules, beadlets or pellets overcome these drawbacks. However, application of controlled release coatings on multiparticulate dosage forms is difficult due to the larger specific surfaces as compared to tablets or capsules. To achieve an evenly distributed coating layer with sufficient thickness, the required amount of coating material is much higher than for tablets or capsules, reducing the available space for payload.

Suitable coating materials for release in the small intestine often comprise pH sensitive polymers. This approach utilizes the existence of the pH gradient in the GIT that increases progressively from the stomach (pH 1.5-3.5) and small intestine (pH 5.5-6.8) to the large intestine (6.4-7.0). The most commonly used pH-dependent polymers are derivatives of acrylic acid and cellulose. Various pH-dependent coating polymers include cellulose acetate phthalate (CAP) (Aquateric®), poly vinyl acetate phthalate (PVAP) (Coaterie), hydroxypropyl methyl cellulose phthalate (HPMCP), and methacrylic acid copolymers, commonly known as methacrylate copolymers or Eudragit.

An important limitation of the pH sensitive coating technique is the uncertainty of the location and environment in which the coating may start to dissolve. It is possible that enteric coating alone may lead to premature drug release in the small intestine due to a variation in GI motility.

The use of GI microflora as a mechanism of drug release in the colonic region has been of great interest to researchers in the past. The majority of bacteria are present in the distal gut although they are distributed throughout the GI tract. The colonic bacteria are predominately anaerobic in nature and secrete enzymes that are capable of metabolizing both endogenous and exogenous substrates such as carbohydrates and proteins that escape digestion in the upper GI tract. Polysaccharides naturally occurring in plant (e.g., pectin,

guar gum, inulin), animal (e.g., chitosan, chondroitin sulfate), algal (e.g., alginates), or microbial (e.g., dextran) origins were studied for colon targeting. These are broken down by the colonic microflora to simple saccharides by saccharolytic species like bacteroides and bifidobacteria. [Jose, S., K. Dhanya, T. A. Cinu, J. Litty and A. J. Chacko (2009). “Colon targeted drug delivery: different approaches.” J. Young Pharm. 1(1): 13-19.].

Although specifically degraded in the large intestine, many of these polymers are hydro-philic in nature, and swell under exposure to upper GI conditions, which leads to premature drug release. Moreover, these fermentable usually show very high viscosity in solution, which makes them difficult or impossible to process in higher concentration.

Fermentable biopolymers have been used as encapsulating matrix. In matrix encapsulation, the active substance is homogenously distributed in a protective matrix, in this case a fermentable biopolymer. However, matrix encapsulation has several serious drawbacks. Due to the high viscosity of the biopolymers, the matrix solution, e.g. in a spray drying or gel encapsulation is very dilute, making it difficult and expensive to dry. Payload in matrix encapsulation is relatively low (typically less than 50%).

Now the goal of the present invention was to find an improved multiparticulate delivery system (formulation) to improve the stability of water-soluble vitamins (i.e. B vitamins (especially B2)) during the transport through the stomach and the small intestine (before being released in the large intestine) so that the availability and the efficacy of water-soluble vitamins (i.e. B vitamins (especially B2)) are improved.

Furthermore, the new delivery system should be producible in a simple and industrial applicable way.

It was found that when a solid core comprising at least one nutraceutical is coated with a specific inner and a specific outer coating, then the delivery system has improved proper-ties. Furthermore, the delivery system can be produced in batch-wise as well as in by continuous process.

The new delivery system (DS) according to the present invention consists of

-   -   (a) a solid core, which comprises at least one water-soluble         vitamin (especially vitamin B2), and     -   (b) an inner coating comprising at least one fermentable         biopolymer, which is crosslinked, and     -   (c) an outer coating which is resistant to stomach conditions         and releasing in the small intestine.

The active substance, which is in the core is a water-soluble vitamin, especially a B vitamin, more preferred it is vitamin B2.

If needed and wished the other nutraceuticals can be incorporated into the core (or the coatings. Nutraceuticals are compounds that provide health benefits in the animal.

Preferred nutraceuticals in the present invention are organic acids, omega 3 fatty acids, omega 6 fatty acids, omega 8 fatty acids, long chain fatty acids, polyphenols (such as resveratrol or genistein), prebiotics, probiotics, essential oils, and antimicrobial peptides.

Therefore, the present invention relates to a delivery system (DS1), which is the delivery system (DS), wherein the solid core comprises at least one nutraceutical is chosen from the group consisting of organic acids, omega 3 fatty acids, omega 6 fatty acids, omega 8 fatty acids, long chain fatty acids, polyphenols (such as resveratrol or genistein), prebiotics, probiotics, essential oils, and antimicrobial peptides.

Preferred organic acids are short chain fatty acids (SCFAs) as well as their salts.

Short-chain fatty acids are fatty acids with two to six carbon atoms. In the context of the present invention SCFAs are the following: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid and salts of these acids. Especially preferred is propionic acid and salts thereof.

The most preferred water-soluble vitamin in the context of the present invention is vitamin B2 (Riboflavin).

Therefore, the present invention relates to a delivery system (DS2), which is the delivery system (DS) or (DS1), wherein the water-soluble is vitamin B2.

Furthermore, another embodiment of the present invention is related to a delivery system, which only comprises vitamin B2 as an active ingredient (nutraceutical), This means the delivery system (solid core and coatings) is free of any other nutraceutical chosen from the group consisting of organic acids, omega 3 fatty acids, omega 6 fatty acids, omega 8 fatty acids, long chain fatty acids, polyphenols (such as resveratrol or genistein), prebiotics, probiotics, essential oils, and antimicrobial peptides.

Therefore, the present invention relates to a delivery system (DS3), which is the delivery system (DS), (DS1) or (DS2), wherein the delivery system (solid core and coatings) is free of any other nutraceutical chosen from the group consisting of organic acids, omega 3 fatty acids, omega 6 fatty acids, omega 8 fatty acids, long chain fatty acids, polyphenols (such as resveratrol or genistein), prebiotics, probiotics, essential oils, and antimicrobial peptides.

The delivery system according to the present invention comprises an inner coating, which needs to fulfill the criteria as defined. Suitable materials for the inner coating (fermentable biopolymer) are for example alginate, chitosan, pectin, cyclodextrin as well as other gums. Preferred coating materials for the inner coating are alginate or pectin.

The inner coating is crosslinked. This can be done by commonly known crosslinking compounds. In case alginate is used that can be done by Mg and/or Ca ion (by the use of a salt). The crosslinker can be spray onto to solid core after having applied the inner coating or simultaneously. Or the coated particles can be dipped into a solution comprising the crosslinker.

Preferably the crosslinker is sprayed onto the particles after having applies the inner coating layer.

Another advantage of the present invention also lies therein that the production of the new delivery system according to the present invention can be done batch-wise as well as continuously. In contrast to the systems known from the prior art this is a huge advantage also in view of the industrial production of such product. The details of the process are disclosed below.

Therefore, the present invention relates to a delivery system (DS4), which is the delivery system (DS), (DS1), (DS2) or (DS3), wherein the material of the inner coating is chosen from group consisting of alginate, chitosan, pectin, cyclodextrin as well as other gums.

Therefore, the present invention relates to a delivery system (DS4′), which is the delivery system (DS4), wherein the material of the inner coating is alginate or pectin.

The inner coating layer is covering the core (more or less) completely. Ideally the (layer of the inner coating has (more or less) the same thickness when applied on the solid core. Usually the thickness of the inner coating layer is at least 5 μm and not more than 20 μm. Preferably, the thickness of the inner coating layer is between 5 μm-10 μm.

Therefore, the present invention relates to a delivery system (DS5), which is the delivery system (DS), (DS1), (DS2), (DS3), (DS4) or (DS4′), wherein the thickness of the inner coating layer is 5 μm-10 μm.

The inner coating layer is crosslinked with at least one crosslinking agent. Any suitable crosslinker can be used. Very suitable (and therefore preferred are Mg and Ca ions (they are added in form of a salt).

Therefore, the present invention relates to a delivery system (DS6), which is the delivery system (DS), (DS1), (DS2), (DS3), (DS4), (DS4′) or (DS5), wherein the inner coating layer is crosslinked with at least one crosslinking agent (preferably with Mg and/or Ca ions).

Therefore, the present invention relates to a delivery system (DS7), which is the delivery system (DS), (DS1), (DS2), (DS3), (DS4), (DS4′), (DS5) or (DS6), wherein the crosslinked inner coating layer is Na alginate or Na pectin.

The delivery system according to the present invention comprises an outer coating, which needs to fulfill the criteria as defined. Suitable materials which fulfill the criteria for the outer coating is for example shellac, methacrylate copolymers and fats.

Therefore, the present invention relates to a delivery system (DS8), which is the delivery system (DS), (DS1), (DS2), (DS3), (DS4), (DS4′), (DS5), (DS6) or (DS7), wherein the material of the outer coating is chosen from group consisting of shellac, methacrylate copolymers and fats.

The outer coating layer is covering the inner coating (more or less) completely. Ideally the layer of the outer coating has (more or less) the same thickness when applied on the inner coating.

Usually the thickness of the outer layer is at least 10 μm and usually less than 30 μm. Preferably, the thickness of the outer coating layer is between 10 and 20 μm.

Therefore, the present invention relates to a delivery system (DS9), which is the delivery system (DS), (DS1), (DS2), (DS3), (DS4), (DS4′), (DS5), (DS6), (DS7) or (DS8), wherein the thickness of the outer coating layer is 10 μm-20 μm.

The solid core of the delivery system according to the present invention is usually 10-85 wt-%, preferably 50-75 wt-%, based on the total weight of the delivery system.

Therefore, the present invention relates to a delivery system (DS10), which is the delivery system (DS), (DS1), (DS2), (DS3), (DS4), (DS4′), (DS5), (DS6), (DS7), (DS8) or (DS9), wherein the solid core of the delivery system is 10-85 wt-%, preferably 50-75 wt-%, based on the total weight of the delivery system.

The inner coating of the delivery system according to the present invention is usually 1-20 wt-%, preferably 1-10 wt-%, based on the total weight of the delivery system.

Therefore, the present invention relates to a delivery system (DS11), which is the delivery system (DS), (DS1), (DS2), (DS3), (DS4), (DS4′), (DS5), (DS6), (DS7), (DS8), (DS9) or (DS10), wherein the inner coating of the delivery system is 10-85 wt-%, preferably 1-10 wt-%, based on the total weight of the delivery system.

The outer coating of the delivery system according to the present invention is usually 1-30 wt-%, preferably 15-30 wt-%, based on the total weight of the delivery system.

Therefore, the present invention relates to a delivery system (DS12), which is the delivery system (DS), (DS1), (DS2), (DS3), (DS3′), (DS3″), (DS4), (DS5), (DS5′), (DS6), (DS7), (DS8), (DS9), (DS10) or (DS11), wherein the outer coating of the delivery system is 1-30 wt-%, preferably 15-30 wt-%, based on the total weight of the delivery system

The delivery system according to the present invention can be up to 2 mm in size. The size is defined by the longest diameter of the particle. The shape of the particle is not an essential feature of the present invention. Also the size distribution of the particles is no essential. The size and the shape of the particle is mainly defined by the solid core of the delivery system. Depending on the use of the delivery system the size can be adjusted.

The delivery system according to the present invention is produced by commonly known technology.

Usually the solid core is produced in a first step and then the inner and outer coatings are applied.

As disclosed above one of the major advantage of the new delivery system (besides the property of the delivery system) lies in the process of production of the delivery system.

The new delivery system can be produced batch-wise of continuously.

When produced batch-wise the new particles can be produce as follows:

In first step the solid core is produced by spray drying process, then in a second step the solid cores (obtained in the first step) are coated by spray coating with the coating material of the inner coating, and then the crosslinker is spray onto the particle. In a third step the outer coating is spray onto the particle obtained by the previous steps and finally the particles are dried.

The advantage of the process is that the steps can be carried in the same apparatus (spray coater) which reduces the technical effort. Nevertheless, it is also possible to i.e. produce the solid cores first, store them and then coat them.

Another option how to produce the new delivery system is a continuous process, wherein the solid cores are produced first and then the coating steps are done spray onto the particle one after the other. These processes are ideal to apply in an industrial scale.

Therefore the present invention also related to a process of production (P) of any of the particles (DS), (DS1), (DS2), (DS3), (DS3′), (DS3″), (DS4), (DS5), (DS5′), (DS6), (DS7), (DS8), (DS9), (DS10), (DS11) or (DS12), wherein the process is carried out batch-wise.

Therefore the present invention also related to a process of production (P1) of any of the particles (DS), (DS1), (DS2), (DS3), (DS3′), (DS3″), (DS4), (DS5), (DS5′), (DS6), (DS7), (DS8), (DS9), (DS10), (DS11) or (DS12), wherein the process is carried out continuously.

The new delivery systems (DS), (DS1), (DS2), (DS3), (DS3′), (DS3″), (DS4), (DS5), (DS5′), (DS6), (DS7), (DS8), (DS9), (DS10), (DS11) and/or (DS12) according to the present invention can be used as such or incorporated into application forms.

The new delivery systems (DS), (DS1), (DS2), (DS3), (DS3′), (DS3″), (DS4), (DS5), (DS5′), (DS6), (DS7), (DS8), (DS9), (DS10), (DS11) and/or (DS12) can used as such in any dietary supplement, food product, feed product, personal care product or pharmaceutical product.

The new delivery systems (DS), (DS1), (DS2), (DS3), (DS3′), (DS3″), (DS4), (DS5), (DS5′), (DS6), (DS7), (DS8), (DS9), (DS10), (DS11) and/or (DS12) can also be part of a premix formulation, which can then be used to formulate any dietary supplement, food product, feed product, personal care product or pharmaceutical product.

The invention also relates to a process for the production of a premix, dietary supplement, food product, feed product, personal care product or pharmaceutical product using at least one delivery system (DS), (DS1), (DS2), (DS3), (DS3′), (DS3″), (DS4), (DS5), (DS5′), (DS6), (DS7), (DS8), (DS9), (DS10), (DS11) or (DS12).

The invention also relates to a premix, dietary supplement, food product, feed product, personal care product or pharmaceutical product comprising at least one delivery system (DS), (DS1), (DS2), (DS3), (DS3′), (DS3″), (DS4), (DS5), (DS5′), (DS6), (DS7), (DS8), (DS9), (DS10), (DS11) or (DS12).

The following examples serve to illustrate specific embodiments of the invention claimed herein. All percentages are given in relation to the weight and all the temperatures are given in degree Celsius.

EXAMPLES Example 1

12 g Na alginate (grinsted sodium alginate) were dissolved in 568 g water at 50° C. with stirring. 1.5 g Ca chloride dihydrate was dissolved in 148.5 g water. 80 g granulated Riboflavin (B2 Universal, DSM) was filled in a fluid-bed processor (WFP mini, DMR, Wurster configuration). All coating steps were performed at a product temperature of about 40° C. The alginate solution was sprayed on the fluidized Riboflavin granulate first. After spraying of the alginate solution, the feeding tube was briefly rinsed with water. The Ca chloride solution was sprayed on the inner coating at 40° C. for hardening. After the hardening solution, 117 g aqueous shellac preparation with a solids content of 25% (Aquagold SSB, Stroever) was sprayed as outer coating. After spraying of the shellac, the product was dried in the fluid bed. 103 g coated granules were obtained.

Composition of the final coated granulate was 60% Riboflavin, 9% alginate, 1% Ca chloride and 30% shellac.

Protection of riboflavin under stomach conditions was tested with 0.1N HCl at 37.5° C. using a USP-4 (SOTAX) apparatus. After 1 hours less than 20% of the riboflavin was released. 

The invention claimed is:
 1. A delivery system of solid particles for the oral delivery of at least one water-soluble vitamin, wherein each of the solid particles consists of: (a) a solid core which includes at least one water-soluble vitamin, (b) an inner coating covering the solid core, the inner coating comprising at least one fermentable crosslinked biopolymer, and (c) an outer coating covering the inner coating, the inner coating being formed of a material which is resistant to stomach conditions so as to be resistant to the release of the at least one water-soluble vitamin within the small intestine.
 2. The delivery system according to claim 1, wherein the solid core comprises vitamin B2.
 3. The delivery system according to claim 1, wherein the inner coating is formed of a material selected from group consisting of alginate, chitosan, pectin, cyclodextrin and other gums.
 4. The delivery system according to claim 1, wherein the inner coating layer is crosslinked with Mg and/or Ca ions.
 5. The delivery system according to claim 1, wherein the outer coating is formed of a material selected from group consisting of shellac, methacrylate copolymers and fats.
 6. A process for the production of a premix, dietary supplement, food product, feed product, personal care product or pharmaceutical product, wherein the process comprises incorporating the delivery system according to claim 1 into a formulation to form the premix, dietary supplement, food product, feed product, personal care product or pharmaceutical product.
 7. A premix, dietary supplement, food product, feed product, personal care product or pharmaceutical product comprising the delivery system according to claim
 1. 8. A process for making the delivery system of claim 1 comprising the steps of: (a) spray-drying an aqueous mixture comprising the at least one water-soluble vitamin to form the solid core; (b) forming the inner coating by spraying the at least one fermentable biopolymer onto the solid core; (c) bringing the inner coating into contact with a crosslinking agent to thereby cross-link the at least one fermentable biopolymer and thereby form a crosslinked inner coating; and thereafter (d) forming the outer coating on the inner coating by spraying a material resistant to stomach conditions onto the crosslinked inner coating.
 9. The process according to claim 8, wherein steps (a)-(d) are practiced continuously or batchwise. 